- Email: [email protected]
Effects of amyloid plaques and ApoE4 allele on brain connectivity in cognitively normal elderly
Poster Presentations P1 patients were presymptomatic with CDR-SOB of zero. Age and sex matched controls (n ¼ 17) were recruited. Results: MAPT mutation carriers who were symptomatic were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) ratio, an index of neuronal integrity, increased myoinositol (mI)/Cr ratio, a marker for glial activity, decreased NAA/mI and hippocampal atrophy (p0.001). Whereas presymptomatic MAPT mutation carriers had elevated mI/Cr and decreased NAA/mI (p0.001), NAA/Cr levels and hippocampal volumes were not different from controls. Decrease in NAA/ Cr (R2 ¼ 0. 33;p ¼ 0.016), NAA/mI (R2 ¼ 0.19;p ¼ 0.078), and hippocampal volumes (R2 ¼ 0.56;p < 0.001) were associated with proximity to the expected or actual age of symptom onset in MAPT mutation carriers. Conclusions: The data suggest an ordered sequencing of the 1H MRS and MRI biomarkers. The neurodegenerative changes that are characterized by an elevation in the glial marker mI/Cr begin years before the onset of symptoms, and the decrease in the neuronal marker NAA/Cr and hippocampal atrophy appear to follow shortly before dementia ensues and become progressively more abnormal as dementia worsens. This sequence of 1H MRS and volumetric MRI changes in MAPT mutation carriers show similarities to the 1H MRS findings in sporadic and familial AD, and is in agreement with microglial activation observed prior to neuronal loss and hippocampal atrophy in tau transgenic mice. These early 1H MRS findings suggest that the mI/Cr ratio may be a useful inclusion biomarker for preventive trials in presymptomatic carriers of MAPT mutations and possibly other proteinopathies. P1-412
EFFECTS OF AMYLOID PLAQUES AND APOE4 ALLELE ON BRAIN CONNECTIVITY IN COGNITIVELY NORMAL ELDERLY
Yvette Sheline, John Morris, Allison Goate, Mark Mintun, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: yvette@ npg.wustl.edu Background: At rest, important brain areas constitute a network with correlated spontaneous brain activity, the ‘‘default mode network’’ (DMN). These regions, including the precuneus, are among the earliest regions affected in Alzheimer’s disease (AD). Both neuropathology and clinical PIB imaging studies support the existence of a pre-clinical AD state with elevated Ab burden in cognitively normal individuals. We sought to determine if the putative toxic effects of Ab plaques extend to differences in functional connectivity between cognitively normal individuals with (PIB+) and without (PIB-) Ab deposition. In addition, we determined the effects of the ApoE4 allele in individuals who were PIB-. Methods: Community-living volunteers enrolled in longitudinal studies of memory and aging at the Washington University Alzheimer’s Disease Research Center (ADRC). In one sample, participants with Alzheimer’s disease (AD) (n ¼ 35) were compared with 68 cognitively normal participants who were further subdivided by PET PIB imaging into those without evidence of brain amyloid (PIB-) and those with brain amyloid (PIB+) deposition. The regions with abnormalities were further applied in a sample of participants divided by ApoE genotype. Resting state fMRI (fcMRI) images were acquired on a 3T scanner and correlation maps were obtained by selecting a seed region in the precuneus and creating an image map of correlations using Pearson product-moment correlation and the voxel-by-voxel BOLD time-course. Results: Resting state fMRI demonstrated that, compared with the PIB- group, the PIB+ group differed significantly in functional connectivity in the same regions, and in the same direction, as differences found in the AD group. Further, examining effects of ApoE4, significant differences were found in bilateral hippocampus and other regions in the default mode network. Conclusions: Our data demonstrate that prior to any manifestations of cognitive or behavioral changes there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Ab toxicity can be detected using resting state fMRI. In addition, examining only PIB- subjects, there was a significant effect of ApoE4 genotype on connectivity, suggesting that even prior to Ab plaque deposition, pathological effects of the E4 allele can be demonstrated.
P1-413
S295 THE FIRST RESULTS OF AMYLOID IMAGING IN JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (J-ADNI) STUDY
Kenji Ishii1, Muneyuki Sakata1, Keiichi Oda1, Kiichi Ishiwata1, Michio Senda2, Kengo Ito3, Ryozo Kuwano4, Takeshi Iwatsubo5 Study Group for the Japanese Alzheimer’s Disease Neuroimaging Initiative1, 1Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Molecular Imaging Research Group, Foundation for Biomedical Research and Innovation, Kobe, Japan; 3Department of Brain Science and Molecular Imaging, National Institute for Longevity Sciences, Obu, Japan; 4Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan; 5Department of Neuropathology and Neuroscience, Tokyo University Graduate School of Medicine, Tokyo, Japan. Contact e-mail: [email protected] Background: Alzheimer’s Disease Neuroimaging Initiative in Japan (J-ADNI) project has been launched enacting a harmonized protocol with US and world-wide ADNI studies. Thirty-eight clinical sites recruit a total of 600 subjects: 300 mild cognitive impairements (MCI), 150 Alzheimer’s disease (AD), and 150 cognitively normals (CN), and candidates of surrogate markers such as MRI, FDG-PET, PiB-PET, BF227-PET, CSF biomarkers are being accumulated. Among registered 296 subjects as of January 2010, amyloid PET was acquired in 45%, and FDG-PET was obtained in 75% of the total participants. Here we demonstrate the first preliminary results of amyloid PET in J-ADNI. Methods: The first 75 baseline PiB scans from 9 PET centers were analyzed with demographic information including APOE genotype. A bolus injection of [C-11]PiB (537 6 70 MBq) was followed by a 70min 3D dynamic scan. A sum image of 50-70 min and a parametric image of distribution volume by Logan graphical analysis were created in each subject, and evaluated in reference to the cerebellar cortex measures, that is SUVR and DVR, for both visual diagnosis and quantitative measurements of neocortical regions. Results: We estimated an optimal cut-off value for SUVR as 1.47, with which the discrimination well corresponds to the visual diagnosis. The prevalence of PiB positivity was 93% in AD (age and ratio of APOE4 carrier; 73 6 5.3, 50.0%), 70% of MCI (71 6 5.6, 57.9%), and 32% of CN (67 6 5.1, 43.8%). The PiB positive ratio in APOE4 carrier in AD, MCI and CN groups were 100%, 100%, and 54%, whereas those in non-carriers remain 88%, 40%, and 22%. A significant positive effect of APOE4 for PiB accumulation was observed even in early 60s (Figure 1). Among 3 cases out of 33 subjects diagnosed as PiB-negative with SUVR images, we found distinct cortical deposition of PiB in DVR images, but none of the reverse. Conclusions: We observed a PiB positive ratio in Japanese population equivalent to the US, Australia and EU studies. A significant APOE4 effect was found to push up amyloid-beta deposition even in young-old subjects. A dynamic PiB-PET analysis may give us more sensitive assessment for a small amount of amyloid deposition. P1-414
IN VIVO NEUROPATHOLOGY OF CORTICAL CHANGES IN INCIPIENT ALZHEIMER’S DISEASE
Annapaola Prestia1, Paul E. Rasser2,3, Matteo Bonetti4, Paul M. Thompson5, Giovanni B. Frisoni1, 1IRCCS - Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; 2Schizophrenia Research Institute, Sydney, Australia; 3University of Newcastle, Newcastle, Australia; 4Istituto Clinico Citta` di Brescia, Brescia, Italy; 5UCLA School of Medicine, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Patients with mild cognitive impairment (MCI) have memory deficits without functional impact on activities of daily living and have a 10fold greater risk of developing Alzheimer’s dementia (AD) in the following 5 years. Neurodegenerative changes in patients with AD at the dementia stage have been well characterized using structural magnetic resonance imaging (MRI) but earlier changes are still relatively poorly understood. Here we aimed to map the cortical changes in MCI patients, a subgroup of whom later developed AD. Methods: Structural T1-weighted high-resolution MR scans were acquired at baseline (T0) and after 1.4 6 0.3 (SD) years (T1) from 46 elderly patients with amnestic MCI (age 69 6 8 years, MMSE 27 6 2).
EFFECTS OF AMYLOID PLAQUES AND APOE4 ALLELE ON BRAIN CONNECTIVITY IN COGNITIVELY NORMAL ELDERLY
Yvette Sheline, John Morris, Allison Goate, Mark Mintun, Washington University School of Medicine, St. Louis, MO, USA. Contact e-mail: yvette@ npg.wustl.edu Background: At rest, important brain areas constitute a network with correlated spontaneous brain activity, the ‘‘default mode network’’ (DMN). These regions, including the precuneus, are among the earliest regions affected in Alzheimer’s disease (AD). Both neuropathology and clinical PIB imaging studies support the existence of a pre-clinical AD state with elevated Ab burden in cognitively normal individuals. We sought to determine if the putative toxic effects of Ab plaques extend to differences in functional connectivity between cognitively normal individuals with (PIB+) and without (PIB-) Ab deposition. In addition, we determined the effects of the ApoE4 allele in individuals who were PIB-. Methods: Community-living volunteers enrolled in longitudinal studies of memory and aging at the Washington University Alzheimer’s Disease Research Center (ADRC). In one sample, participants with Alzheimer’s disease (AD) (n ¼ 35) were compared with 68 cognitively normal participants who were further subdivided by PET PIB imaging into those without evidence of brain amyloid (PIB-) and those with brain amyloid (PIB+) deposition. The regions with abnormalities were further applied in a sample of participants divided by ApoE genotype. Resting state fMRI (fcMRI) images were acquired on a 3T scanner and correlation maps were obtained by selecting a seed region in the precuneus and creating an image map of correlations using Pearson product-moment correlation and the voxel-by-voxel BOLD time-course. Results: Resting state fMRI demonstrated that, compared with the PIB- group, the PIB+ group differed significantly in functional connectivity in the same regions, and in the same direction, as differences found in the AD group. Further, examining effects of ApoE4, significant differences were found in bilateral hippocampus and other regions in the default mode network. Conclusions: Our data demonstrate that prior to any manifestations of cognitive or behavioral changes there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Ab toxicity can be detected using resting state fMRI. In addition, examining only PIB- subjects, there was a significant effect of ApoE4 genotype on connectivity, suggesting that even prior to Ab plaque deposition, pathological effects of the E4 allele can be demonstrated.
P1-413
S295 THE FIRST RESULTS OF AMYLOID IMAGING IN JAPANESE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (J-ADNI) STUDY
Kenji Ishii1, Muneyuki Sakata1, Keiichi Oda1, Kiichi Ishiwata1, Michio Senda2, Kengo Ito3, Ryozo Kuwano4, Takeshi Iwatsubo5 Study Group for the Japanese Alzheimer’s Disease Neuroimaging Initiative1, 1Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; 2Molecular Imaging Research Group, Foundation for Biomedical Research and Innovation, Kobe, Japan; 3Department of Brain Science and Molecular Imaging, National Institute for Longevity Sciences, Obu, Japan; 4Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan; 5Department of Neuropathology and Neuroscience, Tokyo University Graduate School of Medicine, Tokyo, Japan. Contact e-mail: [email protected] Background: Alzheimer’s Disease Neuroimaging Initiative in Japan (J-ADNI) project has been launched enacting a harmonized protocol with US and world-wide ADNI studies. Thirty-eight clinical sites recruit a total of 600 subjects: 300 mild cognitive impairements (MCI), 150 Alzheimer’s disease (AD), and 150 cognitively normals (CN), and candidates of surrogate markers such as MRI, FDG-PET, PiB-PET, BF227-PET, CSF biomarkers are being accumulated. Among registered 296 subjects as of January 2010, amyloid PET was acquired in 45%, and FDG-PET was obtained in 75% of the total participants. Here we demonstrate the first preliminary results of amyloid PET in J-ADNI. Methods: The first 75 baseline PiB scans from 9 PET centers were analyzed with demographic information including APOE genotype. A bolus injection of [C-11]PiB (537 6 70 MBq) was followed by a 70min 3D dynamic scan. A sum image of 50-70 min and a parametric image of distribution volume by Logan graphical analysis were created in each subject, and evaluated in reference to the cerebellar cortex measures, that is SUVR and DVR, for both visual diagnosis and quantitative measurements of neocortical regions. Results: We estimated an optimal cut-off value for SUVR as 1.47, with which the discrimination well corresponds to the visual diagnosis. The prevalence of PiB positivity was 93% in AD (age and ratio of APOE4 carrier; 73 6 5.3, 50.0%), 70% of MCI (71 6 5.6, 57.9%), and 32% of CN (67 6 5.1, 43.8%). The PiB positive ratio in APOE4 carrier in AD, MCI and CN groups were 100%, 100%, and 54%, whereas those in non-carriers remain 88%, 40%, and 22%. A significant positive effect of APOE4 for PiB accumulation was observed even in early 60s (Figure 1). Among 3 cases out of 33 subjects diagnosed as PiB-negative with SUVR images, we found distinct cortical deposition of PiB in DVR images, but none of the reverse. Conclusions: We observed a PiB positive ratio in Japanese population equivalent to the US, Australia and EU studies. A significant APOE4 effect was found to push up amyloid-beta deposition even in young-old subjects. A dynamic PiB-PET analysis may give us more sensitive assessment for a small amount of amyloid deposition. P1-414
IN VIVO NEUROPATHOLOGY OF CORTICAL CHANGES IN INCIPIENT ALZHEIMER’S DISEASE
Annapaola Prestia1, Paul E. Rasser2,3, Matteo Bonetti4, Paul M. Thompson5, Giovanni B. Frisoni1, 1IRCCS - Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; 2Schizophrenia Research Institute, Sydney, Australia; 3University of Newcastle, Newcastle, Australia; 4Istituto Clinico Citta` di Brescia, Brescia, Italy; 5UCLA School of Medicine, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Patients with mild cognitive impairment (MCI) have memory deficits without functional impact on activities of daily living and have a 10fold greater risk of developing Alzheimer’s dementia (AD) in the following 5 years. Neurodegenerative changes in patients with AD at the dementia stage have been well characterized using structural magnetic resonance imaging (MRI) but earlier changes are still relatively poorly understood. Here we aimed to map the cortical changes in MCI patients, a subgroup of whom later developed AD. Methods: Structural T1-weighted high-resolution MR scans were acquired at baseline (T0) and after 1.4 6 0.3 (SD) years (T1) from 46 elderly patients with amnestic MCI (age 69 6 8 years, MMSE 27 6 2).